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Osteogenesis imperfecta: Are fractures and growth hormone treatment linked?
LETTERS
Osteogenesis irnperlecta: Are fractures and growth hormone treatment linked? To the EiJitor: Antoniazzi et al. 1 have reported that growth hormone (GH) treatment does not increase the risk of bone fractures in patients with moderate osteogenesis imperfecta (01). However, in our patient, the number of fractures increased when GH was added to a pamidronate treatment. The patient, a girl whose type I 0 I was diagnosed on the basis of x-ray findings and the presence of blue sclera, had experienced bone fractures 1.4 times per year on average since the age of 1 year. Intravenous administration (15 mg once per month) of bisphosphonate pamidronate, a bone resorption inhibitor, was initiated at 9 years of age when her height and growth velocity were -3.5 SO and 3.4 cm/yr, respectively. For 1 year, no fractures occurred and her height velocity was 4.3 cm/yr. At 10 years of age, G H treatment (0.5 U/kg per week) was initiated in addition to the pamidronate, although the serum insulin-like growth factor I level and bone age were normal. During the 10 months of this combined treatment, her height velocity increased (6.0 cm/yr); however, three bone fractures occurred during the final 5 months. GH therapy was discontinued, but pamidronate was continued. Since then she has had no fractures for 24 months, and her height velocity is 3.9 cm/yr. Serum calcium did not vary significantly during these treatments. Bone density measured by scanning of the lumbar spine was 93, 141,207, and 246 mg/cm 3 before treatment, during pamidronate treatment, during combined therapy, and during subsequent administration of pamidronate alone, respectively. No adverse effects of pamidronate were observed. Bisphosphonate treatment is reported to improve bone manifestations in young patients with 01 or Gaucher's disease. 2,3
Moreover, Valk et al. 4 reported that combined pamidronate and GH treatments benefit bone mineral mass. Therefore the bone fractures that occurred in our patient during treatment were probably related to GH, not the combined therapy. Fujita et al. 5 reported that the frequency of fractures began to increase significantly 2 years after the initiation of G H treatment in a 10-year-old patient with type I Or. These findings indicate that GH therapy may increase the fracture risk in some patients with moderate Or, whereas small doses of pamidronate seem to offer some benefit.
Hiroko Kodama, MD KilZlWki Kubota, MD To.!hiaki Abe, MD Department ofPediatric.! Teikyo UniverJity SchooL ofMedicine Tokyo, Japan 9/35/86231 REFERENCES 1. Antoniazzi F, Bertoldo F, Mottes M, Valli M, Sirpresi S, Zamboni G, et al. Growth hormone treatment in osteogenesis imperfecta with quantitative defect of type I collagen synthesis. J Pediatr 1996; 129:432-9. 2. Huaux JP, Lokietek W. Is APD a promising drug in the treatment of severe osteogenesis imperfecta? J Pediatr Orthop 1988;8:71-2. 3. Samuel R, Katz K, Papapoulos SE, Yosipovitch Z, Zaizov R, Liberman VA. Aminohydroxy propylidene bisphophonate (APD) treatment improves the clinical skeletal manifestations of Gaucher's disease. Pediatrics 1994;94:385-9. 4. Valk NK, Erdtsieck RJ, Algra D, Lamberts SWJ, Pols HAP. Combined treatment of growth hormone and the bisphosphonate pamidronate, versus treatment with GH alone, in GH-deficient adults: the effects on renal phosphate handling, bone turnover and bone mineral mass. Clin EndocrinoI1995;43:317-24. 5. Fujita K, Kizaki Z, Inoue F. Kodo N, Furukawa N, Kinugasa A, et al. A case of osteogenesis imperfecta type IA who accompanied increased frequency of bone fractures by GH therapy. In: Suwa S, ed-
itor. Proceedings of the 4th Meeting of the Research Society for the Growth Disturbance in Children. Tokyo: Jeff Corporation; 1990. p. 173-9.
Reply To tbe EiJitor: My colleagues and I appreciated the opportunity to review the problem of fractures in patients affected by type I osteogenesis imperfecta (01) and treated with growth hormone (GH). Kodama et al. reported the case of a girl treated first with pamidronate and no fractures, who was then treated fora period of 10 months with G H during which 3 fractures occurred, and finally for another 24 months with pamidronate alone during which no fractures occurred. In our study,l in a group of patients with quantitative defect of type I collagen synthesis, selected on the basis of clinical, biochemical, and molecular studies, GH treatment did not increase the fracture risk both in the short- and long-term period. The different behavior is probably related to a coexistence of factors:
1. We must consider that 01 is a heterogeneous congenital disorder of connective tissue classified according to clinical and radiologic features into almost four major subtypes. Also in 01 type I, the mildest form, there is a variable degree in the bone fragility, short stature, and relevance of skeletal deformities. In fact, these children usually have different clinical histories and have undergone different kinds of pharmacologic, rehabilitative, and orthopedic treatments that may also influence growth. So the fracture rate may be very different among patients of the same 01 type (in this case type I 01) but also in the same patient in different periods, depending mainly on motor abilities (muscu-
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Osteogenesis irnperlecta: Are fractures and growth hormone treatment linked? To the EiJitor: Antoniazzi et al. 1 have reported that growth hormone (GH) treatment does not increase the risk of bone fractures in patients with moderate osteogenesis imperfecta (01). However, in our patient, the number of fractures increased when GH was added to a pamidronate treatment. The patient, a girl whose type I 0 I was diagnosed on the basis of x-ray findings and the presence of blue sclera, had experienced bone fractures 1.4 times per year on average since the age of 1 year. Intravenous administration (15 mg once per month) of bisphosphonate pamidronate, a bone resorption inhibitor, was initiated at 9 years of age when her height and growth velocity were -3.5 SO and 3.4 cm/yr, respectively. For 1 year, no fractures occurred and her height velocity was 4.3 cm/yr. At 10 years of age, G H treatment (0.5 U/kg per week) was initiated in addition to the pamidronate, although the serum insulin-like growth factor I level and bone age were normal. During the 10 months of this combined treatment, her height velocity increased (6.0 cm/yr); however, three bone fractures occurred during the final 5 months. GH therapy was discontinued, but pamidronate was continued. Since then she has had no fractures for 24 months, and her height velocity is 3.9 cm/yr. Serum calcium did not vary significantly during these treatments. Bone density measured by scanning of the lumbar spine was 93, 141,207, and 246 mg/cm 3 before treatment, during pamidronate treatment, during combined therapy, and during subsequent administration of pamidronate alone, respectively. No adverse effects of pamidronate were observed. Bisphosphonate treatment is reported to improve bone manifestations in young patients with 01 or Gaucher's disease. 2,3
Moreover, Valk et al. 4 reported that combined pamidronate and GH treatments benefit bone mineral mass. Therefore the bone fractures that occurred in our patient during treatment were probably related to GH, not the combined therapy. Fujita et al. 5 reported that the frequency of fractures began to increase significantly 2 years after the initiation of G H treatment in a 10-year-old patient with type I Or. These findings indicate that GH therapy may increase the fracture risk in some patients with moderate Or, whereas small doses of pamidronate seem to offer some benefit.
Hiroko Kodama, MD KilZlWki Kubota, MD To.!hiaki Abe, MD Department ofPediatric.! Teikyo UniverJity SchooL ofMedicine Tokyo, Japan 9/35/86231 REFERENCES 1. Antoniazzi F, Bertoldo F, Mottes M, Valli M, Sirpresi S, Zamboni G, et al. Growth hormone treatment in osteogenesis imperfecta with quantitative defect of type I collagen synthesis. J Pediatr 1996; 129:432-9. 2. Huaux JP, Lokietek W. Is APD a promising drug in the treatment of severe osteogenesis imperfecta? J Pediatr Orthop 1988;8:71-2. 3. Samuel R, Katz K, Papapoulos SE, Yosipovitch Z, Zaizov R, Liberman VA. Aminohydroxy propylidene bisphophonate (APD) treatment improves the clinical skeletal manifestations of Gaucher's disease. Pediatrics 1994;94:385-9. 4. Valk NK, Erdtsieck RJ, Algra D, Lamberts SWJ, Pols HAP. Combined treatment of growth hormone and the bisphosphonate pamidronate, versus treatment with GH alone, in GH-deficient adults: the effects on renal phosphate handling, bone turnover and bone mineral mass. Clin EndocrinoI1995;43:317-24. 5. Fujita K, Kizaki Z, Inoue F. Kodo N, Furukawa N, Kinugasa A, et al. A case of osteogenesis imperfecta type IA who accompanied increased frequency of bone fractures by GH therapy. In: Suwa S, ed-
itor. Proceedings of the 4th Meeting of the Research Society for the Growth Disturbance in Children. Tokyo: Jeff Corporation; 1990. p. 173-9.
Reply To tbe EiJitor: My colleagues and I appreciated the opportunity to review the problem of fractures in patients affected by type I osteogenesis imperfecta (01) and treated with growth hormone (GH). Kodama et al. reported the case of a girl treated first with pamidronate and no fractures, who was then treated fora period of 10 months with G H during which 3 fractures occurred, and finally for another 24 months with pamidronate alone during which no fractures occurred. In our study,l in a group of patients with quantitative defect of type I collagen synthesis, selected on the basis of clinical, biochemical, and molecular studies, GH treatment did not increase the fracture risk both in the short- and long-term period. The different behavior is probably related to a coexistence of factors:
1. We must consider that 01 is a heterogeneous congenital disorder of connective tissue classified according to clinical and radiologic features into almost four major subtypes. Also in 01 type I, the mildest form, there is a variable degree in the bone fragility, short stature, and relevance of skeletal deformities. In fact, these children usually have different clinical histories and have undergone different kinds of pharmacologic, rehabilitative, and orthopedic treatments that may also influence growth. So the fracture rate may be very different among patients of the same 01 type (in this case type I 01) but also in the same patient in different periods, depending mainly on motor abilities (muscu-
559